Safety and Efficacy of Semorinemab in Individuals With Prodromal to Mild Alzheimer Disease
Authors: Edmond Teng, Paul T. Manser, Karen Pickthorn, Flavia Brunstein, Mira Blendstrup, Sandra Sanabria Bohorquez, Kristin R. Wildsmith, Bali Toth, Michael Dolton, Vidya Ramakrishnan, Ashwini Bobbala, Sietske A. M. Sikkes, Michael Ward, Reina N. Fuji, Geoffrey A. Kerchner, Peter Farnbach, Chris Kyndt, Terence O'Brien, Nawaf Yassi, Raymond Schwartz, Siddhartha Lieten, Rik Vandenberghe, Frederik Vanhee, Richard Bergeron, Sandra Black, Sharon Cohen, Andrew Frank, William Nisker, Maria Carmela Tartaglia, Annette Justesen, Peter Alexandersen, Soren Nielsen, Anna Areovimata, Pierre Anthony, Serge Belliard, Frédéric Blanc, Mathieu Ceccaldi, Bruno Dubois, Pierre Krolak-Salmon, Hélène Mollion, Florence Pasquier, Timo Grimmer, Monika Elisabeth Kottke-Arbeiter, Christoph Laske, Oliver Peters, Dörte Polivka, Christine von Arnim, Giuseppe Bruno, Carlo De Lena, Emanuele Cassetta, Diego Centonze, Giancarlo Logroscino, Paul Dautzenberg, Sterre Rutgers, Niels Prins, Maciej Czarnecki, Jacek Dobryniewski, Jan Ilkowski, Gabriela Klodowska, Anna Krygowska-Wajs, Robert Kucharski, Anatol Mickielewicz, Marcin Ratajczak, Marzena Zboch, Tomasz Zielinski, Pedro Abizanda Soler, Eduardo Agüera Morales, Miquel Baquero Toledo, Rafael Blesa González, Mercè Boada Rovira, Antonio Del Olmo Rodriguez, Jerzy Krupinski, Gurutz Linazasoro Cristobal, Jesús López Arrieta, Mario Riverol Fernandez, Raquel Sanchez Del Valle Diaz, Félix Viñuela Fernandez, Michael Jonsson, Henrik Östlund, Josephine Emer MacSweeney, Catherine Mummery, Marc Agronin, Thomas Ala, Wendy Bond, Frederick Schaerf, Mark Brody, Keith Edwards, Concetta Forchetti, Ajay Sood, David Geldmacher, Mark Goldstein, Ira Goodman, David Hart, Lawrence Honig, William Justiz, Allan Levey, Scott Losk, Gad Marshall, Walter Martinez, Peter McAllister, William Alvin McElveen, Orlando Maldonado-Robles, Cynthia Murphy, Malini Nair, Anil Nair, Omid Omidvar, Nader Oskooilar, Anton Porsteinsson, Michael Rosenbloom, David Russell, Seyed Ahmad Sajjadi, Aimee Pierce, Stephen Salloway, Sharon Sha, Raj Shah, Sanjiv Sharma, William Smith, Lee Stein, John Stoukides, Stephen Thein, Raymond Turner, David Watson, David Weisman
Journal: JAMA Neurology (2022)

<h3>Importance</h3> Neurofibrillary tangles composed of aggregated tau protein are one of the neuropathological hallmarks of Alzheimer disease (AD) and correlate with clinical disease severity. Monoclonal antibodies targeting tau may have the potential to ameliorate AD progression by slowing or stopping the spread and/or accumulation of pathological tau. <h3>Objective</h3> To evaluate the safety and efficacy of the monoclonal anti-tau antibody semorinemab in prodromal to mild AD. <h3>Design, Setting, and Participants</h3> This phase 2 randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted between October 18, 2017, and July 16, 2020, at 97 sites in North America, Europe, and Australia. Individuals aged 50 to 80 years (inclusive) with prodromal to mild AD, Mini-Mental State Examination scores between 20 and 30 (inclusive), and confirmed β-amyloid pathology (by positron emission tomography or cerebrospinal fluid) were included. <h3>Interventions</h3> During the 73-week blinded study period, participants received intravenous infusions of placebo or semorinemab (1500 mg, 4500 mg, or 8100 mg) every 2 weeks for the first 3 infusions and every 4 weeks thereafter. <h3>Main Outcomes and Measures</h3> The primary outcomes were change from baseline on the Clinical Dementia Rating–Sum of Boxes score from baseline to week 73 and assessments of the safety and tolerability for semorinemab compared with placebo. <h3>Results</h3> In the modified intent-to-treat cohort (n = 422; mean [SD] age, 69.6 [7.0] years; 235 women [55.7%]), similar increases were seen on the Clinical Dementia Rating–Sum of Boxes score in the placebo (n = 126; Δ = 2.19 [95% CI, 1.74-2.63]) and semorinemab (1500 mg: n = 86; Δ = 2.36 [95% CI, 1.83-2.89]; 4500 mg: n = 126; Δ = 2.36 [95% CI, 1.92-2.79]; 8100 mg: n = 84; Δ = 2.41 [95% CI, 1.88-2.94]) arms. In the safety-evaluable cohort (n = 441), similar proportions of participants experienced adverse events in the placebo (130 [93.1%]) and semorinemab (1500 mg: 89 [88.8%]; 4500 mg: 132 [94.7%]; 8100 mg: 90 [92.2%]) arms. <h3>Conclusions and Relevance</h3> In participants with prodromal to mild AD in this randomized clinical trial, semorinemab did not slow clinical AD progression compared with placebo throughout the 73-week study period but did demonstrate an acceptable and well-tolerated safety profile. Additional studies of anti-tau antibodies may be needed to determine the clinical utility of this therapeutic approach. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT03289143